Proj.1 Immunization strategies to elicit bNAbs against HIV-1 PI: Bjorkman, P.J./Nussenzweig, M.C. ! Summary AIDS is a preventable disease, however, according to UNAIDS, millions of people are newly infected every year. The design of a vaccine for HIV-1 is therefore highly desirable. To date, despite numerous efforts, no immunization regimen reproducibly elicits broadly neutralizing antibodies (bNAbs) against HIV-1. Recently available native-like Env trimers do elicit antibodies that neutralize autologous tier-2 viruses but these antibodies have only limited potency and breadth. The observation that most of the native-like Env proteins do not bind the inferred germline (iGL) antibody precursors of bNAbs suggested that rationally designed iGL targeting immunogens would be required to initiate bNAb responses. The Nussenzweig lab has confirmed this hypothesis in knock in mice that carry the iGL PGT121 bNAb which targets the base of the V3 loop and surrounding glycans (V3/N332). Immunization with iGL targeting proteins followed by a series of more native- looking Env trimers elicited bNAbs in iGL PGT121 bNAb knock-in mice. The long term goal of the proposed research is to extend these studies to other animal models that more closely resemble a human immune response and also to other types of bNAbs such as the IOMA-like bNAbs targeting the CD4bs. To accomplish these goals Dr. Nussenzweig will work with Dr. Bjorkman to design and test new immunogens and immunization strategies to elicit V3/N332 and IOMA-like bNAbs in knock-in mice, wild type mice and mice that carry un-rearranged human immunoglobulin loci. The Nussenzweig lab plans to: 1) optimize the previous immunization protocol designed to elicit PGT121-like bNAbs; 2) extend the use of this immunization regimen to other iGL bNAb knock-in mice targeting the V3/N332 site such as the BG18GL mice; 3) design a consensus series of immunogens that elicits the class of V3/N332 bNAbs; 4) design immunization strategies that elicit IOMA-like CD4bs antibodies in IOMAGL knock-in mice; 5) extend these immunization experiments to wild type mice and mice that carry un-rearranged human immunoglobulin loci; 6) evaluate the suitability of the new immunogens to isolate bNAb precursors from healthy donors. The proposed experiments will produce candidate immunogens for vaccine clinical trials. !